Abstract: Autism and autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental diseases where different gene combinations may play a role in different individuals. Nevertheless, the study of mutations in specific genes is helping to characterize the molecular mechanism responsible for subtle alterations in the nervous system, perhaps pointing to a general mechanism for the disorder. Here, we propose a novel approach to study ASD. Using Rett syndrome (RTT) as a pilot disease, we developed an in vitro system deriving induced pluripotent stem cells (iPSCs) from RTT patients'fibroblasts. RTT patients have several autistic features and are part of ASD. RTT patients have defined mutations in the X-linked gene encoding the methyl-CpG binding protein 2 (MeCP2). RTT patients'reprogrammed cells can generate human neurons carrying different types of MeCP2 mutations. Deep sequencing will be used to analyze gene expression during the transition steps of differentiation, simulating early stages of human neural development. The system will allow us to study the relationship of gene expression of coding and non-coding RNAs to the cellular and network phenotypes, such as neuronal arborization, synapse formation and network electrophysiology. Moreover, we will use a chimeric brain system to study the effects of environment in human RTT neurons. In a future step, we will repeat the strategy using different single-gene mutations that also lead to the autistic diagnosis. The data generated will help to reveal and understand possible common mechanisms present in ASD. Public Health Relevance: The goal of this proposal is to develop a cellular model to study Autism Spectrum Disorders using induced pluripotent stem (iPS) cells. We will determine the correlation between gene expression and neuronal phenotype from neurons derived from reprogrammed normal and patient cells. The outcome of this study will increase our understanding of the mechanism behind autism, allowing better diagnoses and new therapeutic interventions.